Investigating the link between REV-ERB and HIF-1a in Th17 cell function

研究 Th17 细胞功能中 REV-ERB 和 HIF-1a 之间的联系

• 批准号: 10721581
• 负责人: Kristine Griffett
• 金额: $ 7.12万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-11 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721581
• 关键词: Adaptive Immune System; Affect; African American; American; Autoimmune Diseases; Binding; Biological Assay; Biological Response Modifier Therapy; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cells; ChIP-seq; Chronic; Chronic Disease; Colitis; Complex; Crohn' s disease; Data; Development; Disease; Drug Targeting; EP300 gene; Ensure; Equilibrium; Exons; Experimental Autoimmune Encephalomyelitis; Feedback; Future; Gene Targeting; Genes; Genetic Transcription; Genus Hippocampus; Glycolysis; Health Care Costs; Hispanic; Human; IL17 gene; Immune; Inflammation; Inflammatory; Insulin-Dependent Diabetes Mellitus; Interleukins; Knockout Mice; Life; Ligand Binding; Ligands; Link; Luciferases; Mediating; Metabolic; Metabolic Pathway; Microbe; Multiple Sclerosis; Mus; Native Americans; Nuclear Receptors; Pathogenicity; Patients; Physiological; Play; Population; Process; Promoter Regions; Protons; Psoriasis; Regulation; Reporting; Repression; Reproducibility of Results; Research Project Grants; Resistance; Response Elements; Rheumatoid Arthritis; Role; T cell regulation; T-Cell Activation; T-Lymphocyte; Therapeutic; Transcriptional Activation; Transcriptional Regulation; United States; Woman; Work; Yin; autoimmune pathogenesis; cancer immunotherapy; cost; cost effective treatment; cytokine; drug discovery; gene repression; graduate student; health care availability; health disparity; insight; interest; novel; novel therapeutics; promoter; recruit; reduce symptoms; targeted treatment; transcription factor

SUMMARY Autoimmune diseases (i.e., rheumatoid arthritis (RA), Type I Diabetes mellitus (T1DM), multiple sclerosis (MS), Crohn's disease, etc.) affect at least 3% of the US population, although this number appears to be significantly increasing since 2020. Interestingly, many autoimmune diseases occur disproportionately in women. These diseases are chronic, debilitating, and often, life threatening. Recent advances in biologic therapeutics have been successful in reducing symptoms of these chronic diseases in many patients. However, due to the costs associated with these treatments, many Americans still go untreated. In fact, several recent reports have described health disparities in women of Hispanic, African American, and Native American descent, due to availability of healthcare and cost-effective therapies. There is a clear unmet need for lower cost therapeutics for autoimmune diseases. To develop new therapies for autoimmune diseases, we need to further our understanding of the physiological and cellular mechanisms controlling activation and differentiation of Th17 cells. Th17 cells are a subtype of CD4+ lymphocytes that produce the pro-inflammatory cytokine interleukin 17a (IL-17a). Dysregulated activity of Th17 cells is associated with several autoimmune diseases including multiple sclerosis, rheumatoid arthritis, psoriasis, and others. Many of the current biologic therapies target the interleukins produced by Th17 cells to reduce aberrant inflammatory processes. HIF-1 is a transcription factor that plays an important role in the metabolic regulation of Th17 cells. Interestingly, the nuclear receptor REV- ERB, regulates both the Th17 cell activation and differentiation by competing with RORt, and recent work by our lab indicates that REV-ERB may directly repress the expression of HIF-1, providing a “two-hit” mechanism to suppressing T-cell mediated autoimmune diseases. This proposal aims to investigate the role that REV-ERB plays in HIF-1 expression and determine the cellular changes that occur in T-cells during activation with and without the presence of REV-ERB ligands. The data obtained from this work will provide novel insights to the role that REV-ERB plays in T-cell physiology, and provide preliminary data for future drug discovery efforts.

概括 自身免疫性疾病（即类风湿性关节炎 (RA)、I 型糖尿病 (T1DM)、多发性硬化症 (MS)、 克罗恩病等）影响着至少 3% 的美国人口，尽管这个数字似乎显着 自 2020 年以来不断增加。有趣的是，许多自身免疫性疾病在女性中发病率不成比例。这些 疾病是慢性的、使人衰弱的，并且常常危及生命。生物治疗学的最新进展 已成功减轻许多患者的这些慢性疾病的症状。但由于成本问题 与这些治疗相关的，许多美国人仍然没有得到治疗。事实上，最近的几份报告已经 描述了西班牙裔、非裔美国人和美洲原住民后裔妇女的健康差异，原因是 医疗保健和具有成本效益的治疗方法的可用性。对低成本疗法的需求显然尚未得到满足 用于自身免疫性疾病。为了开发自身免疫性疾病的新疗法，我们需要进一步研究 了解控制 Th17 激活和分化的生理和细胞机制 细胞。 Th17 细胞是 CD4+ 淋巴细胞的一种亚型，可产生促炎细胞因子白细胞介素 17a (IL-17a)。 Th17 细胞活性失调与多种自身免疫性疾病相关，包括多种自身免疫性疾病 硬化症、类风湿性关节炎、牛皮癣等。目前许多生物疗法的目标是 Th17 细胞产生的白细胞介素可减少异常炎症过程。 HIF-1 是一种转录因子 在 Th17 细胞的代谢调节中发挥重要作用。有趣的是，核受体 REV- ERB 通过与 RORt 竞争来调节 Th17 细胞的活化和分化，最近的工作 我们的实验室表明REV-ERB可能直接抑制HIF-1α的表达，提供“二次打击”机制 抑制 T 细胞介导的自身免疫性疾病。本提案旨在调查 REV-ERB 的作用 在 HIF-1 表达中发挥作用，并确定 T 细胞在激活和 过程中发生的细胞变化 不存在 REV-ERB 配体。从这项工作中获得的数据将为 REV-ERB 在 T 细胞生理学中发挥的作用，并为未来的药物发现工作提供初步数据。